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Current Issues in Molecular Biology Nov 2023NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune... (Review)
Review
NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.
PubMed: 37998739
DOI: 10.3390/cimb45110562 -
Haematologica Jun 2024STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms...
STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms are largely unknown. We conducted a multicenter study on a series of 82 myeloid neoplasms with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutations in myeloid neoplasms was low, <0.5%, but mutations were detected in all categories of such neoplasms, including myelodysplastic syndrome (MDS, 28%), acute myeloid leukemia (AML, 26%), myelodysplastic/myeloproliferative neoplasm (MDS/MPN, 18%), Philadelphia chromosome-negative classic MPN (12%), systemic mastocytosis (1%), and, with a notably high frequency, chronic eosinophilic leukemia, not otherwise specified (CEL-NOS, 15%). STAT5B mutations occurred preferentially in the SH2 domain (95%), involved 12 different codons, with the N642H hotspot being the most common (78%). Co-mutations were present in all cases and clonal hierarchy analysis showed that STAT5B mutations tended to be subclonal in AML, MPN, and MDS, but frequently dominant/co-dominant in CEL-NOS (83%), followed by MDS/MPN (40%). Across the group, eosinophilia and/or basophilia were common (41%), frequently observed in cases in which STAT5B mutations were detected at initial diagnosis (P<0.0001), with a high variant allele frequency (median 42.5%, P=0.0001), as a dominant/ co-dominant clone (P<0.0001), involving the canonical N642H (P=0.0607), and associated with fewer co-mutations (P=0.0009). Our data show that the characteristics and importance of a STAT5B mutation differ among myeloid neoplasms, but if present as a dominant mutation and detected at initial diagnosis, it appears to be a driver mutation in a subgroup of chronic myeloid neoplasms, preferentially promoting a proliferation of eosinophils and basophils.
Topics: Humans; STAT5 Transcription Factor; Mutation; Eosinophilia; Male; Female; Middle Aged; Aged; Basophils; Adult; Myeloproliferative Disorders; Aged, 80 and over; High-Throughput Nucleotide Sequencing; Myelodysplastic Syndromes
PubMed: 37981812
DOI: 10.3324/haematol.2023.284311 -
BioRxiv : the Preprint Server For... Oct 2023Eosinophilic esophagitis (EoE) is diagnosed and monitored using esophageal eosinophil levels; however, EoE also exhibits a marked, understudied esophageal mastocytosis.
BACKGROUND
Eosinophilic esophagitis (EoE) is diagnosed and monitored using esophageal eosinophil levels; however, EoE also exhibits a marked, understudied esophageal mastocytosis.
OBJECTIVE
Using machine learning, we localized and characterized esophageal mast cells to decipher their potential role in disease pathology.
METHODS
Esophageal biopsy samples (EoE, control) were stained for mast cells by anti-tryptase and imaged using immunofluorescence; high-resolution whole tissue images were digitally assembled. Machine learning software was trained to identify, enumerate, and characterize mast cells, designated Mast Cell-Artificial Intelligence (MC-AI).
RESULTS
MC-AI enumerated cell counts with high accuracy. During active EoE, epithelial mast cells increased and lamina propria (LP) mast cells decreased. In controls and EoE remission patients, papillae had the highest mast cell density and negatively correlated with epithelial mast cell density. Mast cell density in the epithelium and papillae correlated with the degree of epithelial eosinophilic inflammation, basal zone hyperplasia, and LP fibrosis. MC-AI detected greater mast cell degranulation in the epithelium, papillae, and LP in EoE patients compared with control individuals. Mast cells were localized further from the basement membrane in active EoE than EoE remission and controls individuals but were closer than eosinophils to the basement membrane in active EoE.
CONCLUSION
Using MC-AI, we identified a distinct population of homeostatic esophageal papillae mast cells; during active EoE, this population decreases, undergoes degranulation, negatively correlates with epithelial mast cell levels, and significantly correlates with distinct histologic features. Overall, MC-AI provides a means to understand the potential involvement of mast cells in EoE and other disorders.
CLINICAL IMPLICATION
We have developed a methodology for identifying, enumerating, and characterizing mast cells using artificial intelligence; this has been applied to decipher eosinophilic esophagitis and provides a platform approach for other diseases.
CAPSULE SUMMARY
A machine learning protocol for identifying mast cells, designated Mast Cell-Artificial Intelligence, readily identified spatially distinct and dynamic populations of mast cells in EoE, providing a platform to better understand this cell type in EoE and other diseases.
PubMed: 37961565
DOI: 10.1101/2023.10.25.563471 -
Diagnostics (Basel, Switzerland) Oct 2023Our knowledge of biology and mast cell (MC) function, as well as disorders associated with the pathologic activation of MCs, has evolved over the last few decades.... (Review)
Review
Our knowledge of biology and mast cell (MC) function, as well as disorders associated with the pathologic activation of MCs, has evolved over the last few decades. Anaphylaxis, mast cell activation syndrome (MCAS), and mastocytosis are interrelated yet distinct conditions within the spectrum of mast cell activation disorders. Nevertheless, all three conditions can co-exist in one and the same patient, as pathologic MC activation is the key finding in all three. When mediator release is excessive and involves multiple systems, anaphylaxis and MCAS may occur. Furthermore, mastocytosis is a clonal disorder of MCs and often presents with anaphylaxis and MCAS. Nevertheless, in some cases, even the proliferative and accumulative features of MCs in mastocytosis can account for symptoms and disease progression. In each case, diagnosis can be only made when the diagnostic consensus criteria are fulfilled. The current article aims to provide a concise clinical update and pinpoint the main difficulties in diagnosing these puzzling disorders of MCs in medical practice.
PubMed: 37958203
DOI: 10.3390/diagnostics13213307 -
Therapeutic Advances in Hematology 2023In systemic mastocytosis, cytoreductive treatment is indicated for advanced systemic mastocytosis (AdvSM) variants. The treatment scenario is rapidly diversifying...
In systemic mastocytosis, cytoreductive treatment is indicated for advanced systemic mastocytosis (AdvSM) variants. The treatment scenario is rapidly diversifying especially with the introduction of KIT tyrosine kinase inhibitors. Avapritinib is a second-generation potent and selective inhibitor of the mutant D816V that, based on the results of pivotal clinical trials, was approved for the treatment of adults with AdvSM by the regulatory agencies US FDA and EMA. The present article reports the experience of treating SM patients with avapritinib in an Italian compassionate use program. The data from our case series confirm the drug as being active after multiple lines of treatment allowing rapid achievement of profound responses, making it also an effective bridging strategy to allogeneic transplant in eligible patients. However, the anticipated wider use of avapritinib in the near future will require careful monitoring of side effects, especially in heavily pretreated patients.
PubMed: 37929078
DOI: 10.1177/20406207231205643 -
Frontiers in Immunology 2023
Topics: Humans; Mast Cells; Mastocytosis; Cell Physiological Phenomena
PubMed: 37928555
DOI: 10.3389/fimmu.2023.1303726 -
International Journal of Molecular... Oct 2023Advanced systemic mastocytosis (SM) is a heterogeneous group of myeloid neoplasms characterized by an uncontrolled expansion of mast cells (MC) in one or more internal... (Review)
Review
Advanced systemic mastocytosis (SM) is a heterogeneous group of myeloid neoplasms characterized by an uncontrolled expansion of mast cells (MC) in one or more internal organs, SM-induced tissue damage, and poor prognosis. Advanced SM can be categorized into aggressive SM (ASM), MC leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). In a vast majority of all patients, neoplastic cells display a mutation, mostly D816V and rarely other variants. Additional mutations in other target genes, such as , , or , may also be identified, especially when an AHN is present. During the past 10 years, improved treatment approaches have led to a better quality of life and survival in patients with advanced SM. However, despite the availability of novel potent inhibitors of KIT D816V, not all patients enter remission and others relapse, often with a multi-mutated and sometimes D816V-negative disease exhibiting multi-drug resistance. For these patients, (poly)chemotherapy, antibody-based therapies, and allogeneic hematopoietic stem cell transplantation may be viable treatment alternatives. In this article, we discuss treatment options for patients with drug-resistant advanced SM, including novel KIT-targeting drugs, antibody-based drugs, and stem cell-eradicating therapies.
Topics: Humans; Quality of Life; Mastocytosis; Mastocytosis, Systemic; Mast Cells; Mutation; Proto-Oncogene Proteins c-kit
PubMed: 37894806
DOI: 10.3390/ijms242015125 -
Current Oncology (Toronto, Ont.) Oct 2023Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of... (Review)
Review
Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a alteration (NM_000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.
Topics: Female; Humans; Child; Adolescent; Congenital Microtia; Mastocytosis, Systemic; Mastocytosis; Mastocytosis, Cutaneous; Proto-Oncogene Proteins c-kit
PubMed: 37887549
DOI: 10.3390/curroncol30100649 -
Acta Parasitologica Dec 2023The association of fever, focal hepatic lesions and peripheral hyper-eosinophilia (FHLH) can be observed in both infectious and non-infectious conditions. Fascioliasis,...
BACKGROUND
The association of fever, focal hepatic lesions and peripheral hyper-eosinophilia (FHLH) can be observed in both infectious and non-infectious conditions. Fascioliasis, capillariasis, toxocariasis, all causes of visceral larva migrans (VLM), represent most of the former, whilst lymphomas, eosinophilic leukemias and mastocytosis belong in the non-infectious conditions.
METHODS
We prospectively followed a young patient presenting with FHLH in the Tuscany region of Italy.
RESULTS
The patient was subject to serological and parasitological examination in an attempt to clarify the origin of the lesions. Serologies for both Fasciola hepatica and Toxocara spp. were positive, with the latter presenting a higher index. We opted for treatment with a prolonged course of albendazole due to the serological results and being toxocariasis more frequent in our setting. The patient was then subject to radiological follow-up. The patient responded to treatment with albendazole as shown by a decrease in eosinophils, seronegativization for Toxocara spp., clinical and radiological improvement. Toxocariasis was hence considered the most likely diagnosis.
CONCLUSIONS
Parasitic infections cannot be disregarded in the presence of FHLH. Differential diagnosis between these parasitic infections can be challenging due to the presence of similar clinical presentations and serological cross-reactions, and follow-up of the patient is needed to ensure optimal treatment outcomes.
Topics: Animals; Humans; Larva Migrans, Visceral; Toxocariasis; Albendazole; Toxocara; Eosinophils
PubMed: 37872438
DOI: 10.1007/s11686-023-00723-9